### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C

. 20460



### M E MORAND U M

D ate: 23 Mar ch 20 1 6 O F FIC E O F CH EMI CAL SAFETY A N D PO L L UT IO N PRE VE N T I ON

S U BJ EC T: T ri adimefo n and Tr i ad im eno l

. H uman H ealth Assessment Scoping Document in Support of Re g i st r at i on Review.

PC Co des: I 0990 I (t ri adimefon)

, 12720 I (t riadim e n ol) D ecis i o n No .: 5 1105 7 Petiti o n No.: NA Ri sk Assessment Type: Single Chem i ca l

, Agg r egate TXR No

. : NA

MRJD No.: NA DP Barcode: 0430121 R

egist rati on Nos.: Multip l e Regulatory Action: Registration Review Case No.: 2700 CAS No.: 43121

- 43-3 (t r iadimefon)

, 55219

- 65-3 (triadimenol) 40 CFR: 180.410 (triadimefon), 1 80.450 (tr i ad im eno l )



### FROM: Michael 

### A. Doherty

, Ph.D.

, Chem i st

# ~~~ Kar l yn Middleton, M.S., To x i co logi st 

# ,?,

Zaida I. Figueroa, DrPH

, I ndustrial Hygienist · ·' Health Effects Division (7509P) 

# +.A μ

Nathan Mott!

, Biologist -\-:::

# ~=--,__,..?-""---. Jonathan L eshin

, PhD

, Toxicolog i st Ri sk Assess m ent Science Support B ra Antimicrobial s Division (AD, 75 lOP )

THR U : Je ss Ro wland, Depu ty Director Jeff Dawson

, Deputy Director (acti 0 

# r-;**~** H ealth Effects Division (7509 P ) 

# r

_ 

# ,,..- -" --k-- \'- 

# s w S te ven Weis s, Branch Chief 1

-

## ~~ Tim othy Leighton

, Senior Scientist 

# I

- KJ. -... RA S S B / AD (75 1 OP)



### TO: Christina Motilall/Tom Moriarty/Ne il Anderson Ri sk Management and Impl e m e ntation Branch I P esticide Re-Evaluation Di vis i on (7508P)

Ra che l Ric c i a rdi

, Che mical R ev i ew M a n ager Antimicrobial s Division (A D

, 751 OP)

Pag e I of34The Health Effect s Divis i on (HED) and Antimicrob ial s Di v i s ion (AD) have joint l y prepared a human h ea lth risk assessment scop in g document for triadimefon and triadimenol to support registration review. HED reviewed the conventional us es and AD revi e wed the antimicrobial uses of these pesticides. Thi s document summar i zes the evaluation of the data ava ilable for assessing human health risk from exposure to triadimefon and triadimenol

, as well as any data needed to s upport registration review.



### Executive S umm ary

Triadirnefon and triadirnenol are triazol e- derivative fungicides. Triadimenol i s a metabolite of triadimefon and i s also a regi ste red active ingredi e nt. Triadimefon is r eg istered for use as a wood preservative. which is considered an antimicrobial u se, and as a conventional fungicide for u se

on pine seeds / seed lin gs, Christmas tre es, ornamental planting s and land scapes (exterior / interior)

, and turf in commercia l and r es idential settings. Triadimenol is registered as a fungicide for see d

treatment on barley. corn, cotton
, oats. rye, so rghum

, and wheat. In addition

, there is a tolerance without a US regi s tration for r es idues in/on banana.

The toxicology database for triadimefon is comp l e te with th e exception of the subc hroni c inhalation toxicity s tud y

. The study i s required based on hi g h inhalation risk estimates for several
exposure scenarios ( TXR #0057320)

. The inhalation risk estimates are s till of concern for some convent i onal- u se scenarios even with the use of additional p e rsonal protection equ ipment (P P E;

s uch as PFS or PF IO respirators) and e ngineerin g controls. In the absence of the inhalation

s tudy

, a l 

### OX databa se uncertainty factor s hould be retained fo r inhalati on exposure only. The toxicology database for triadim enol, a metabolite of triadimefon is complete and no additional studies are required (TXR#0077332).

The residue chemistry databa se for triadimefon and triadimenol is not complete. The Agency had previously required stud ie s r eflecti n g m e tabolism in cereal and cotton follow in g seed treatment
, and a number of additional st udies were being r ese rved pending the outcome of the required metaboli s m study ( triadimenol Tolerance Reasse ssme nt Eligibility D ec i sio n (TRE D ); 0314891

, 17 November 2005 ). Although the metabolism studies were s ubmitted

, they were found to be unacceptable by HED. Upon further consideration of t h e available data

, HED will use the re s ults from confined rotational crop stud ie s a l ong with the available metaboli sm studies to e lu cidate metabolism in cereals and cotton following seed tr ea tment. Neve rthel ess, the re s idue chemistry database r ema in s incomplete due to th e need for limited field accumu l ation in rotational crop residue s tudies (OCSPP Guideline 860.1900) which were also required in the triadimenol TRED. Extensive field r otational crop residues stud ies ma y also be required, depending on the re sul ts from th e limited studies.

ln April

, 2009 ( D351282 ), AD evaluated the pot e ntial risk from exposure to triadimefon a l one;

no risk est imates of concern were identified. In Augus t
, HED (035 1080 ) evaluated the potential risk from the combined exposure to triadimefon and triadimenol. In that assessment
, aggregate margin s of exposure ( MOEs ) we r e of concern (i

. e., the MO Es were below the level of concern , or LO C); however

, the risk est imates were characterized as being not of concern due to the conservative assumptions u sed in the assessment.

Page 2 of34

### Page 3 of 34

In evaluating the data available for triadimefon and triadimenol, HED and AD have identified
t he following data needs for triadimefon (which will be bridged, as needed, to triadimenol)

, noting that analysis of both triadimefon and triadimenol should be include d in any studies involving residue analysis : HED Data Needs for Tri a dimefon:

 A 90

- day inha lation toxicity study (OCSPP Guideline 870.3465)

 A limited field rotational crop study (OCSPP Guideline 860.1900) and potentially an extensive field rotational crop study.

 A dislodgeable foliar residue study (OCSPP Guideline 875.2100) may be required pend ing a determination of the registration status of the use on pineapple. AD Data Needs for Triadimefon :

 D ermal (Guideline 875.1200) and inhalation (Guideline 875.1400) surrogate applicator exposure studies (mixing/loading wettable powders, dip/spray sapstain, and wood pressure treatment)

.

 P roduct use data (Guideline 875.1700) to clarify uses, application rates (wood retentions), and application equipment

.

 W ipe studies (Guideline 875

. 2300) for treated decks at the highest wood retention rate.

To date, OPP has not conducted an aggregate assessment for triadimefon/triadimenol that considers both the antimicrobial and conventional pesticide uses. During registration review, HED/AD will conduct new dietary, residential, aggregate, and occupational risk ass essments incorporating all registered uses of these compounds (both antimicrobial and conventional)

, using the existing data and the newl y required toxicity and exposure studies

.

Introduction

The triazole

- derivative fungicides triadimefon and triadimenol are scheduled for registration review by the Office of Pesticide Programs. This scoping document identifies the current state of the hazard and exposure databases for these compounds, any studies that are necessary to bring those databases up to current s tandards, and the anticipated work to be done by the Health Effects and the Antimicrobials Division s in order complete a human health risk assessment under registration review

.

In addition to be ing an active ingredient, triadimenol is a major metabolite of triadimefon , and the toxicological effects associated with these compounds are the same . As a result, triadimefon and triadimenol are assessed together by combining exposure estimates from each compound. The last comprehensive risk assessment was conducted in conjun c tion with reregistration in 2006 ( D331455 , 1 August 2006 ), following the triadimefon Reregistration Eligibility Decision ( RED ) / triadimenol TRED, in respo nse to mitigation measures resulting from the triadimefon RED. Subsequent to that assessment, HED conducted an abbreviated assessment to evaluate reinstating the use on residential turf (D351080, 3 August 2009).

At the time of the last assessment, triadim efon was registered for use as a fungicide on pine seed/ seedlings, Christmas trees, ornamental plantings, landscapes (exterior/interior) , and residential and commercial turf

, and pineapple (post

- harvest dip and seed

- piece treatment) , and triadi menol was re gistered for use as a seed treatment on barley, corn, cotton, oats, rye, sorghum,

### Page 4 of 34

and wheat , resulting in tolerances for residues in/on commodities of those crops . In addition, there is a tolerance for residues in/on banana without a US registration (i.e., an “import tolerance”)

. It is HED’s understanding that since the last risk assessment the uses of triadimefon on pineapple have been cancelled by the registrant. If the pineapple uses of triadimefon have not been cancelled, then a dislodgeable foliar resi due study (OCSPP 875.2100) is required. In April 2009

, triadimefon was assessed by the Antimicrobials Division for use as a wood preservative , and there are currently three registered products that contain approximately 45

- 49% triadimefon. These products a re formulated as a wettable powder, a ready

- to

- use solution, and a soluble concentrate.

In developing this scoping document, the most recent human health risk assessments have been relied on along with the existing toxicology, residue chemistry, and o ccup ational/residential exposure databases for triadimefon and triadimenol.

Hazard Identification/ Toxicology

The toxicology database for triadimefon is complete with the exception of the subchronic inhalation toxicity study. Inhalation risk estimates of conc ern were identified using the oral point of departure ( POD ) currently selected for risk assessment at baseline level clothing (i.e., long

sleeves shirt, long pants, shoes plus socks) with no respiratory protection which is consistent with the current labels . Additional PPE is needed to obtain acceptable risk estimates ( i.e., PF 5 or PF 10 respirators, or engineering co ntrols). However, i nhalation risks of concern still exist with the use of additional PPE for granules applied aerially (applicator MOE=220 with engineering controls , with an LOC of 1

, 000 ) and for wettable powders using a mechanically

pressurized handgun in greenhouses (mixer/loader/applicator MOE=570 with a PF10 respirator). Therefore, the Hazard Science Policy Council (HASPOC) determined that an inhalation toxicity study is needed for triadimefon. In the absence of the inhalation toxicity study, a 10X data base uncertainty factor should be retained only for inhalation exposure. An immunotoxicity study is also not available for triadimefon; however, the HASPOC determined that the study is not required, based on a weight of evidence approach, considering the a vailable hazard and exposure information ( TXR #0057320 ). The HASPOC also determined that missing studies for triadimenol (a metabolite of triadimefon), including acute and subchronic neurotoxicity, inhalation, and metabolism studies are not needed because t hese data gaps are satisfied by st udies with triadimefon (TXR#00 7 73 2 2) . Therefore, the toxicology database for triadimenol is complete and no additional studies are required

.

For both t riadimefon and triadimenol, neurotoxicity and liver effects were consistently observed in oral and dermal toxicity studies. For triadimefon, several neurobehavioral findings (FOB, hyperactivity, increased auditory startle reflex, changes in body temperature and motor activity) were observed after oral and dermal exposur e in guideline studies

. Effects on the liver were seen in toxicity studies in rats and mice including changes in liver enzymes, increased organ weights, hypertrophy, and histopathology

. Long

- term exposure to triadimefon led to an increased incidence of hep atocellular adenomas in mice and thyroid adenomas in rats

. Consequently, triadimefon is classified as a "possible human carcinogen." A nonlinear approach was considered appropriate for assessing cancer risk to triadimefon since the thyroid adenomas seen we re borderline in terms of statistical significance and, despite the presence of hepatocellular

### Page 5 of 34

adenomas in both sexes of mice, all of the tumors associated with the active ingredient were benign. Finally, there is no mutagenicity concern for triadimefon.

For triadimenol, neurotoxic effects including changes to behavioral characteristics, motor activity, and spontaneous activity were observed in a special acute neurotoxicity study with rats and mice

. Limited neurotoxicity was observed in the guideline neuro toxicity studies for triadimenol

. However, there are data from the literature that highlight a neurotoxic concern for triadimenol after repeated exposure

. Effects on the liver in rats, mice and dogs included increased organ weights, elevated enzymes, hyper trophy, and/or histopathology changes. Long

term exposure led to an increased incidence of hepatocellular adenomas in females only

. Triadimenol is classified as 

### Group C, “possible human carcinogen,” based on an increased incidence of hepatocellular adenoma s in female mice only. A nonlinear approach was considered appropriate for assessing cancer risk to triadimenol since the tumors observed were benign and only seen in one sex. Additionally, there is no mutagenicity concern for triadimenol.

There was evidence of quantitative and/or qualitative susceptibility seen in developmental and reproduction studies for both triadimefon and triadimenol

. For triadimefon, skeletal effects (incomplete ossification of pelvis pubes, phalanges, and irregular spinous pro cess on the scapula) were seen in the rabbit developmental study and abnormal ribs and distended urinary bladder were observed in one of two rat developmental studies . The effects in rat and rabbit fetuses were seen in the absence of treatment related mate rnal effects

. Additionally, decreased pup weight, deviated snout, and clinical signs (incr eased auditory startle, and # trials to criterion in pass avoidance test) were observed in offspring animals in the presence of less severe maternal toxicity (decreas ed body weight) in the reproduction study. For triadimenol, extra ribs were observed in fetuses in a rat developm ental study in the presence of non

- treatment related effects on body weight (decreased <10%)

. There is low concern for the susceptibility obs erved in the triadimefon/triadimenol studies since clear NOAELs were determined for the effects seen and because the current points of departure are protective of the effects. Therefore, the FQPA factor has been reduced to 1x for both chemicals.

Both t riadimefon and t riadimenol have low toxicity in acute lethality studies via the oral, dermal, and inhalation routes of exposure (Toxicity Category III and IV) . They are not dermal irritants (Category IV) or sensitizers. Triadimefon is slightly irritating t o the eye (Category IV), while triadimenol is an eye irritant (Category II)

. Endpoints and PODs for both triadimefon and triadimenol dietary assessments are based on triadimefon data since the chemicals have a similar structure, toxicity profile, and mode of action

. For acute and chronic dietary exposure, the triadimefon subchronic neurotoxicity (SCN) study was used with a NOAEL of 3.4 mg/kg/day, based on hyperactivity observed at the LOAEL of 54.6 mg/kg/day

. Although an acute neurotoxicity study is al so available for triadimefon, the SCN study was considered appropriate for assessing both acute and chronic dietary scenarios since the NOAELs were similar in the studies and there was no progression in toxicity with increased duration (similar LOAELs)

. Th e oral SCN study was also used for assessing risks associated with triadimefon inhalation exposure

. For dermal exposure, a dermal toxicity study

### Page 6 of 34

was used with a NOAEL of 300 mg/kg/day, based on neurotoxic effects (increased reactivity and activity) observe d at the limit dose of 1000 mg/kg/day

. For triadimenol, previous risk assessments did not address worker exposure. Therefore, endpoints and PODs for these scenarios will be selected during registration review

. No residential exposure is expected for triadi menol; long

- term exposures are not anticipated for triadimefon or triadimenol based on the registered use patterns

. Since the last risk assessment for triadimefon, food uses for the active ingredient have been cancelled. Therefore, dietary exposure is no longer anticipated for triadimefon and this should be reflected in future risk assessments. For triadimenol, future risk assessments should use the acute neurotoxicity ( ACN ) study with a slightly lower POD (as compared to the SCN) to assess acute dietary exposure to protect for effects observed in the special acute CNS study. The SCN study is still appropriate for assessing chronic dietary exposure.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals

. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity

. These studies i nclude endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring

. Fo r ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups

. As part of the most recent registration decision for triadimenol and triadimefon, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), triadimenol and triadimefon are subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP)

.

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator
may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemi cals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list

### Page 7 of 34

of chemicals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

Triadimefon is on List 1 for which EPA has received all of the required Tier 1 assay data

. The Agency has reviewed all of the assay data received for the appropriate List 1 chemicals and the conclusions of those reviews are available in the chemical

- specific public dockets (see Docket No. EPA

- HQ

- OPP

- 2005

- 0258 ) for triadimefon. Triadimenol was not included on either the first or second list.

Conclusions fo r Hazard Identification/Toxicology

An inhalation toxicity study is needed for triadimefon

, based on unacceptable inhalation risk estimates for several scenarios. Unacceptable risk estimate s still exist for some scenarios with additional PPE (i.e., PF 10 respirator) and/ or engineering controls ; current labels don’t require respiratory protection . In the absence of the study, a 10X database uncertainty factor should be retained for inhalation exposure only.

The toxicology database for triadimenol is compl ete, and no new data are needed . However, endpoints and PODs for worker scenarios should be selected for triadimenol during registration review . Also, the triadimefon ACN study (instead of the SCN) should be used to assess acute dietary exposure for triadi menol to protect for effects observed in the special acute CNS study.

The endpoints, points of departure and safety f actors used for risk assessment should also be reexamined based on current HED policy, as well as any new data received.

Dietary Exposur e

Conventional Uses

Adequate studies are available depicting the metabolism of triadimefon in crops and livestock, a suitable method is available to assess compliance with tolerances, and the available residue data (field trials, processing studies, feed ing studies ) are acceptable and are supported by appropriate analytical method and storage stability studies. The residue chemistry database for triadimefon is complete.

Adequate metabolism data for triadimenol , extrapolated from triadimefon, are available to understand the nature of the residue in plants following foliar application , in livestock, and in rotational crops; however, suitable studies depicting the metabolism of triadimenol in cereal grains and cotton following seed treatment are not available. The need for these studies was identified in the TRED for triadimenol ( D3 14891

, 17 November 2005 ) . The studies were submitted and reviewed by HED in 2009 (D349015, 4 August 2009)

. The submitted studies (in winter wheat, spring wheat, and sp ring barley) were determined to be unacceptable

. However,

u pon further evaluation of the available data, HED has determined that metabolism studies conducted as seed treatment are no longer needed

.

1 http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074

### Page 8 of 34

The confined rotational crop study conducted with triadi mefon included wheat as a rotational crop. That study was found to be suitable for extrapolation to satisfy the requirement for a confined rotational crop study with triadimenol. Since the environmental conditions in a confined rotational crop study mimic those that would be encountered in a seed

- treatment metabolis m study, and the results from the foliar crop metabolism and confined rotational crop studies result in a similar profile of residues, HED concludes that the metabolism in crops is adequately und erstood for foliar as well as seed

- treatment applications of triadimefon and triadimenol.

With that determination, the studies being reserved ( storage stability for field corn, sweet corn, cotton, and wheat forage, hay, straw, and processed commodities ; a nd analytical methods ) are also no longer needed

. However, t he residue chemistry database for triadimenol is still not complete. The confined rotational crop study demonstrated that residues persist to a degree that tolerances for inadvertent residues may be required. Therefore, limited and possibly extensive rotational crop studies, conducted according to OCSPP Guideline 860.1900, are required.

Dietary risk estimates in the last risk assessment (D351080, 3 Au g ust 2009) , reflecting conventional uses of tri adimefon and triadimenol, were not of concern (<10% aPAD and <5% cPAD).

HED notes that uses of triadimenol on pineapple appear to have been cancelled; however, language still exists on the labels of three technical products ( EPA Reg. Nos. 264

- 736, 264

- 740, and 81964

- 4) indicating that the product can be used to formulate end

- use products intended for use on pineapple. Such references on the technical product label should be deleted.

Antimicrobial Uses

EPA has not established tolerances or toleranc e exemptions for residues for the antimicrobial uses of triadimefon and triadimenol. Triadimefon and triadimenol ha ve not been cleared as food additive s by the US Food and Drug Administration (US FDA) under the Federal Food, Drug, and Cosmetic Act (FFDCA) Section 409. The only antimicrobial FIFRA

- registered uses of triadimefon and triadimenol are as wood preservative s (wood

- base composite products; wood products for above ground and in

- ground contact; reconstituted wood

- based composite products; and veneer

- based wood products). These uses are not expected to result in direct or indirect dietary (food) exposure; therefore, a dietary exposure assessment is not necessary for the antimicrobial uses of triadimefon and triadimenol.

A qualitative drinking water ri sk assessment was conducted in 2009 (D351279) for the wood preservative use. The drinking water assessment concluded that drinking water concentrations are negligible and that a drinking water assessment is not necessary for wood preservative uses

.

Conclu sion s for Dietary Assessment

During registration review, HED will complete a new dietary risk assessment in order to address results from the required rotational crop study and to update the assessment to the most recent

### Page 9 of 34

dietary consumption database. That dietary assessment will likely necessitate new estimates for residues in drinking water from the Environmental Fate and Effects Division.

Residential Exposure

There is potential for residential exposure to triadimefon associated with handler activities from the registered residential uses on turf (lawns) and garden/trees (o rnamentals ) ; residential handler exposures are not expected from uses as a wood preservative

. Post

- application ex posures may occur from the lawn, ornamental, and wood

- preservative use s of triadimefon, and that exposure may be to the parent compound and/or to triadimenol.

Although triadimenol is not registered for any use sites that will result in residential exposure from the direct application of triadimenol, residential post

- applica tion exposure to triadimenol
may occur via application of triadimefon . Since triadimefon and triadimenol share the same toxicological points of departure, the post

- application assessment for triadimefon address es any exposures that may occur to triadimenol as well.

Residential Handlers

Triadimefon

Homeowners might be exposed to triadimefon when they handle turf and garden/trees products for the control of fungal diseases i n residential settings

. Triadimefon may be applied as water

dispersible granules ( WDG )

, water

- soluble packets ( WSP ) , and /or granular ( G ) formulations in residential settings using handheld equipment (i.e., backpack sprayer and manually

- pressurized handwand), hose

- end sprayer or g ranule spreaders (e.g., belly grinder, shaker can, rotary push

type spreader, etc.). Based on the registered use pattern, the duration of exposure for residential handlers is expected to be short

- term (i.e., 1 to 30 days) in duration. I ntermediate

- term (i .e., 1 to 6 months) and l ong

- term exposures ( i.e., greater than 6 months) are not anticipated. Residential handler exposures were previously assessed as part of the 2006 RED ( D314814, D315040

, S. Recore, 06/30/ 2006 ). In 2009, the Agency conducted a revised residential assessment for the use of triadimefon on residential lawns/turf and determined that the turf use c ould be reinstated (D351080, Z. Figueroa, 08/03/2009)

. Residential handler risk estimates are not of concern.

In conjunction with determining da ta needs during registration review, triadimefon was reviewed by HASPOC to evaluate the need for a route

- specific inhalation study, as previous assessments were conducted using data from an oral study. As noted above, the HASPOC recommended that inhalation toxicity study is needed based on occupational handler risk estimates . In preparation for the HASPOC meeting, inhalation risk estimates were also calculated for residential handlers using current SOPs and exposure assumptions. Residential handler inhalati on risk estimates were not of concern (MOEs>2,100).

Th e most recent residential handler exposure assessment s do not reflect the policies of the HED’s 2012 Residential Standard Operating Procedures (SOPs), but did not identify risks of concern. For registr ation review, HED anticipates that the handler exposure assessment will need to be updated to reflect current exposure assumptions and procedures for residential assessment

### Page 10 of 34

(e.g., HED’s 2012 Residential SOPs for Treated Turf and Gardens and Trees ). However , no risks of concern are expected.

Triadimenol

There are no residential use sites registered for triadimenol; therefore, an assessment of residential handler exposure is not necessary.

Residential Post

- A pplication

Turf and Ornamental Uses

Adults and children can be exposed to post

- application residues of triadimefon on treated turf

. In assessing post

- application exposures to triadimefon, HED has assumed such exposures occur on the day of treatment

. P ost

- application exposures to adults and children from treated turf ( i.e., dermal, and hand

- to

- mouth, objects

- to

- mouth, and ingestion of contaminated soil for children only ) were previously assessed using chemical

- specific transferable turf residue (TTR) data and the SOPs For Residential Exposure Assessme nt . The results of the previous residential post

application exposure assessment indicated that risks are not of concern (MOE > 100) ( D351080, Z. Figueroa, 08/03/2009 )

. In addition, post

- application exposure can result from conducting activities in previ ously treated

areas (e.g., gardening ) . The 2006 RED considered post

- application exposure to adults and children from treated areas such as gardens and trees ( D314814, D315040

, S. Recore, 06/30/ 2006 )

. This assessment indicated that there were no risk estima tes of concern associated with residential post

- application garden/trees scenarios

. In conjunction with determining data needs for registration review, r evised dermal post

- application risk estimates were calculated for occupational handlers conducting pos t

- application activities using current policies and exposure assumptions. Since the estimated residential post

- application exposure for residential garden/ trees using default DFR values for triadimefon is minimal in comparison to the level of concern (i.e. , the calculated MOE is greater than 2 times higher than the level of concern, MOE

= 470 compared to the LOC of 100 ); the 40CFR DFR data requirement is not needed for triadimefon . In this instance, it is unlikely that chemical

- specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for triadimefon

.

Th e most recent residential post

- application exposure assessment s do not reflect the policies of the HED’s 2012 Residential Standard Operating Procedures (SOPs), but did not identify risks of concern. For registration review, HED anticipates that the pos t

- application exposure assessment will need to be updated to reflect current exposure assumptions and procedures for residential assessment (e.g., HED’s 2012 Residential SOPs for Treated Turf and Gardens/Trees ).

Wood

- Preservative Uses

AD has determined that a residential post

- application assessment is ne eded to determine risk for children playing on pressure treated playsets and decks. Compared to adults, c hildren are more

### Page 11 of 34

likely to display higher c ontact activities with wood surfaces (e.g., pressure tre ated wood playset structures), and have a higher surface area to body wei ght ratio. The potential outdoor residential post

- application exposure pathways are outlined below:

• Dermal contact with triadimefon

- treated wood products (e.g., residential playgrou nd equipment and decks); and,

• Incidental ingestion due to hand

- to

- mouth contact with triadimefon

- treated wood products.

A deterministic screening

- level assessment was developed by EPA in 2009 to assess children’s exposure using a surrogate assumption th at the wood residue concentration would be 1 μ g/cm 2 

### (D351282). A confirmatory wood wipe study (GDLN 875.2300) was required as a condition of registration to determine the surface residues of triadimefon over time

, to provide adequate residue data to verify the bounding estimate and to refine the risk assessment. The Agency has not received these data. OPP will conduct a more refined assessment, based on the measured surface residues of triadimefon and triadimenol , during registration review.

For the wood

- p reservative uses, residential i nhalation exposure is considered negligible based on the low vapor pressure of triadimefon (less than 1 x 10

- 6 

### mm Hg).

Spray Drift and Volatilization

– Conventional Uses

Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of the conventional applications of triadimefon

. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently

. The approach is outlined in the revised (2012) Standard Operating Procedures f or Residential Risk Assessment (SOPs)

– Residential Exposu re Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift

. This document outlines the quantification of indirect

non

- occupational exposure to drift

. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 2



### . During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies,
route

- specific inhalation toxicological studies) or further analysis is required for triad imefon

.
Conclusions for Residential Assessments

The residential exposure database is adequate to support the existing triadimefon registrations

. HED previously conducted residential handler and post

- application assessments for the uses on turf and gardens/trees. The risk estimates were not of concern. However, during registration review, HED will update these assessments as needed based on revised toxicity endpoints, updated exposure assumptions, and the revised 2012 Residential SOPs. The need for spray drift

2 Volatilization Screening Tool Analysis available at: http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

2014

- 0219.

### Page 12 of 34

and volatilization risk assessment s for triadimefon will be also be examined during registration review.

AD requires a wood wipe study (GDLN 875.2300) for pressure treated decks for registration review for triadimefon and triadimenol. Upon receipt of the requested wood wipe data, AD will conduct a refined residential post

- application risk assessment for children for triadimefon/triadimenol , in support of the wood preservative uses

.
Aggregate Risk Assessment

Aggregate risk estimates for ac ute and chronic exposure to triadimefon and triadimenol are equivalent to the dietary risk estimates and are not of concern. S hort

- term aggregate risk estimates were provided in the most recent risk assessment (D351080, 3 Au g ust 2009). Margins of exposure for adults were not of concern. The MOEs for infants , children 1

- 2 years old, and children 3

- 5 years old ranged from 92 to 94. Although these MOEs were less than the level of concern of 100, they were characterized as being not of concern due to the conser vatisms in the endpoint selection, including the weight of evidence for doses eliciting the neurotoxic effect selected for the risk assessment endpoint. HED notes that the past aggregate assessments for triadimefon/triadimenol do not include sources of exp osure from the use of triadimefon as a wood preservative.

During registration review, HED and AD will provide an updated aggregate risk assessment which takes into account the conventional and antimicrobial uses of both compounds.

Occupational E xpos ure

Triadimefon

In occupational settings for conventional uses , triadimefon may be applied by aerial equipment (sod grass only), airblast (tree nursery/Christmas tree farms), groundboom, tractor spreader, handheld equipment (e.g., backpack sprayer, mechanically

- pressurized handgun, manually

pressurized handwand), or a ready

- to

- use microinjection. There is potential for occupational exposure associated with handler activities (i.e., mixing, loading, and applying) as well as with post

- application activities (i.e., re

- entering treated areas). Occupational exposures are a lso expected for handlers working in commercial/nursery seed treatment operations (e.g., loader/applicator, sewer, bagger, multiple activities workers, and planters) treating pine seeds. It is HED’s understanding that a ll food uses for triadimefon have bee n cancelled. Based on the conventional use sites and use pattern s , the duration s of exposure are expected to be short

- and intermediate

- term. Long

- term exposures (i.e., more than 6 months of continuous exposure) are not expected to occur.

For uses as a wo od preservative, occupational scenarios included mixing and loading wettable powders; and pressure and sapstain ( dip and spray) applications. Under these scenarios, short

- , intermediate

- , and long

- term exposures are expected to occur.

### Page 13 of 34

Occupational Handler s

Conventional Uses

The 2006 RED evaluated a number of occupational handler scenarios that represented the major triadimefon occupational handler exposures based on application equipment and formulation type using the Pesticide Handler Exposure Database ( PHED ); D314814, D315040

, S. Recore, 06/30/ 2006). That assessment indicated that occupational handler non

- cancer scenarios resulted in risk estimates that were not of concern assuming baseline clothing and/or some level of mitigation (i.e., additional pers onal protective equipment (PPE) ) for a number of occupational handler scenarios.

For occupational handlers working in commercial seed treatment operations (D326678, R. Griffin, 02/09/2006), the dermal risk estimates were not of concern for all registered uses at some level of risk mitigation (i.e., chemical

- resistant gloves or apron). For commercial seed treatment, inhalation MOEs were of concern for two scenarios even with maximum inhalation risk mitigation of engineering controls or a 90% protection fac tor half

- face respirator.

In conjunction with determining data needs for registration review, triadimefo n was reviewed by HED’s HASPOC to evaluate the need for a route

- specific inhalation study because previous assessments were conducted using data from an oral study. Revised inhalation risk estimates were calculated for occupational handlers using current po licies, commercial seed treatment methodologies and exposure assumptions. Short

- and intermediate

- term occupational handler inhalation MOEs ranged from 11

– 570,000 ; a number of occupational handler scenarios have inhalation risk estimates of concern (MOEs< 1

, 000) at baseline the level of mitigation (i.e., no respirator). N one of the registered labels currently require any inhalation PP E (i.e., respirator)

. Additional personal protective equipment (PPE) is necessary to obtain risk estimates above the LOC ( i. e., PF 5 or PF 10 respirators, or engineering controls for a number of scenarios ). However, even with additional PPE, inhalation risk estimates were still of concern for handlers applying granules aerially (applicator MOE=220 with engineering controls) and for handlers applying wettable powders using a mechanically

- pressurized handgun in greenhouses (mixer/loader/applicator MOE=570 with a PF10 respirator). All the MOEs for seed treatment handlers wearing label

- required PPE (i.e., single layer + gloves for l oader/applicator and multiple activities worker; single layer + no gloves for sewer and bagger) are greater than 1,100 and are not of concern.

Based on existing registrations, previous risk assessments identified most of the anticipated occupational handl er exposure scenarios

, and estimated risks were not of concern. However, since the 2006 RED new exposure data and updated commercial seed treatment methodologies are available to assess exposure to occupational handlers. Because of these changes, HED will likely conduct an updated occupational handler assessment for triadimefon. Additionally, all occupational handler scenarios will need to be reassessed to address updates to HED’s exposure

### Page 14 of 34

policies, including updates to default exposure data used for handle r scenarios and assumptions for body weights, a s well as any revised toxicity endpoints and PODs

.

Wood

- Preservative Uses

For registration review, t he Agency will need new surrogate data to assess handler exposures of wood preservatives ( mixing/loading we ttable powders for composite wood, dip and spray sapstain treatments and pressure treatments). Surrogate dermal and inhalation proprietary unit exposure data generated by the Antimicrobial Exposure Assessment Task Force II (AETF) and Sapstain Industry Grou p (SIG) would fulfill the data requirement for these assessments. AD no longer accepts Chemical Manufacturers Association ( CMA ) data for registration review. Both the AEATF and SIG require compensation for the proprietary use of their unit exposure data. Upon receipt of th e data, AD will conduct new risk assessments. In registration review,

a pplicator product use data (875. 1700) are needed to clarify uses, application rates (wood retentions), and application equipment (verify composite, sapstain and wood pressure treatments). The duration s of exposure for the occupational uses for workers at wood treatment plants are considered to be short (1 to 30 days), intermediate (30 days to 6 months), and long

term (> 6 months).

Occupational Post

- A pplication

Conven tional Uses

The 2006 RED evaluated a number of occupational post

- application scenarios that represented the major triadimefon occupational post

- application exposure scenarios based on the registered uses. That assessment relied o n default assumptions and the Agricultural Reentry Task Force (ARTF) since n o chemical

- specific dislodgeable foliar residue (DFR) data were available. All occupational post

- application exposure scenarios were not of concern at day 0 (i.e., 12 hours after application) for all post

- a pplication activities. C hemical

- specific transferable turf residue (TTR) data is available to evaluate post

- application exposures from treated turf/sod.

In conjunction with determining data needs for registration review, r evised dermal post

application risk estimates were calculated for occupational handlers conducting post

- application activities using current policies and exposure assumptions. In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use s ites) uses that could result in post

- ap plication exposure to foliage. In the absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a numb er of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the A gricultural Re

- entry Task Force (ARTF) has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pi nching in a Gr eenhouse” (MRID 45344501). As a result, the range of F AR 

### values was revised

### Page 15 of 34

from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as acti ve ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering D FR data for a single chemical. At this time, the ARTF submission did not alter the selection of 25% as the reaso nable, high

- end default value. Because DFR data are not available for triadimefon , EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for triadimefon (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value ), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment methodology will more than compensate for this potential uncertainty. For example, when assessing residential and occupational post

- application exposure to gardens and ornamentals, EPA assumes the following:
exposures occur to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same post

- application activities performed in the transfer

coe fficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage in these post

- application activities for a high

- end amount of time every day (represented by data reflecting time spent gardening based on survey data). Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the highest estimated occupational p ost

- application exposure using default DFR values for triadimefon is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 2 times higher than the level of concern, MOE = 430 compared to the LOC of 100 ); HED determined tha t the 40CFR DFR data requirement is not needed for triadimefon . In this instance, it is unlikely that chemical

- specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availabilit y of dislodgeable foliar pesticide residues for triadimefon.

Since the previous review, there have been several updates to HED’s exposure policies, including updates to post

- application transfer coefficients, transferable residue assumptions and assumptio ns for body weights. Thus, these post

- application scenarios will need to be updated in the Registration Review risk assessment to reflect current policies and updated exposure data.

Wood

- Preservative Uses

AD does not anticipate the need to conduct a n occupational post

- application exposure
assessment. Data from AEATF and SIG cover all worker exposures ( i.e., combines both handler and post

- application exposures) . If new policies or procedures arise , the Agency may revisit the need for a quantitative occu pational post

- application inhalation exposure assessment for triadimefon.

### Page 16 of 34

Triadimenol

Occupational Handler s

Triadimenol is registered for use in the United States for seed treatment (only) in barley, corn, cotton, oats, rye, sorghum, and wheat. Formulations registered include emulsifiable concentrate (EC), wettable powder (WP), flowable concentrate (FlC), and soluble concentrate (SC). As there are no other registered uses for triadimenol, occupational assessment by AD during registration review i s not necessary.

Occupational exposures are expected for handlers working in commercial seed treatment operations (e.g., primary handlers such as l oader/applicator, sewer, bagger and multiple activities workers ) as well as second a ry handlers such as plant ers). Occupational p ost

- appl ication occupational exposures are not of concern for any of the registered uses of triadimenol. Based on the use pattern, occupational short

- and intermediate

- term dermal and inhalation exposures are anticipated. Long

- term expo sures (i.e., more than 6 months of continuous exposure) are not expected to occur

. There is the potential for dermal and inhalation exposure to occupational handlers from the currently registered use pattern of triadimenol. The most recent assessment (D326716, R. Griffin

, 02/09/2006 ) conducted in conjunction with the Tolerance Reassessment Eligibility Decision (TRED) document for triadimenol, did not address worker exposures to triadimenol. However, quantitative dermal and inhalation exposures were pre viously assessed as part of reregistration for occupational handlers working in commercial seed treatment operations for triadimefon (e.g., primary handlers such as loader/applicator, sewer, bagger and multiple activities workers) as well as secondary hand lers such as planters ; D326678 , R. Griffin, 02/09/2006 ). All the appropriate scenarios were assessed. The dermal risk estimates were not of concern for all registered uses at some level of risk mitigation (i.e., chemical

- resistant gloves or apron ). For

com mercial seed treatment, inhalation MOEs were of concern for two scenarios (even with maximum inhalation risk mitigation of engineering controls or a 90% protection factor half

- face respirator).

Since an inhalation study is not available for triadimenol, H ED’s HASPOC evaluate d the need for a route

- specific inhalation study. Using an oral study, inhalation risk estimates were calculated for occupational handle rs using current policies , commercial seed treatment methodologies and exposure assumptions. Short

- and intermediate

- term occupational handler inhalation MOEs were not of concern (> 1,000). The lowest MOE was 1,200 for workers conducting multiple activities for the registered seed treatment uses on corn and cotton with no respirator

. Although no risks of concern were identified for occupational handler scenarios previously assessed for triadimefon

, a quantitative occupational handler exposure assessment is anticipated under registration review . The risk assessment will include both triadimefon and triad imenol, and will incorporate revisions to the Agency’s scenario

- specific surrogate handler exposure data, updated exposure methodologies related to commercial seed treatment, any potential updates to points of departure and to body

- weight assumptions

.

### Page 17 of 34

Oc cupational Post

- A pplication

As the only registered uses of triadimenol are for seed treatment, occupational post

- application exposures are not expected.

Conclusions for Occupational Exposure and Risks

Updated occupational handler exposure assessments will be conducted during registration review for both triadimefon and triadimenol based upon revisions to the Agency’s scenario

- specific surrogate handler exposure data , revised surrogate unit exposure valu es, and updated exposure methodologies related to commercial seed treatment and policies related to secondary handlers for seed treatment

. An updated occupational post

- application assessment will be conducted during registration review to: 1) assess foliar applications of triadimefon to ornamentals (cut flowers) based on revisions to transfer coefficients, transferable residue and body weight assumptions; 2) incorporate the TTR data based on existing and anticipated occupational post

application risk estima tes for treated turf/sod ; and 3) incorporate revised toxicity endpoints.

Public Health and Pesticide Epidemiology Data D431445 , E. Evans and S. Recore, 2 February 2016 D431446 , E, Evans and S. Recore, 2 February 2016

Based on the low frequency and severity of incident cases reported for triadimefon and triadimenol in both the Incident Data System (IDS) and the Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases, there does not appear to be a concern at this time th at would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk
assessment.

Tolerance Assessment and International Harmonization

Triadime fon : A permanent tolerance for residues of triadimefon (as triadimefon plus triadimenol, expressed as triadimefon) in/on pineapple is currently listed in 40 CFR 180.410. It is HED’s understanding that the use on pineapple has been cancelled and that this e ntry can be deleted ; furthermore, the labels for three technical products ( EPA Reg. Nos. 264

- 736, 264

- 740, and 81964

- 4) should be revised to remove the reference to products for treatment of pineapple

. If the entry is retained, the tolerance expression will need to be updated to the current format in order to address coverage and compliance.

Triadimenol : Permanent tolerances for residues of triadimenol (as triadimenol plus its butanediol metabolite cal culated as triadimenol) are listed in 40 CFR 180.450. Listings address barley, corn, oat, rye, wheat, and cotton commodities. In addition, there is a listing without a U.S. registration for residues in/on banana. During registration review, the tolerance e xpression will need to be updated to the current format in order to address coverage and compliance. In addition, HED will likely recommend that the entry itself be revised to be in terms of “Triadimenol” rather than by its chemical name.

### Page 18 of 34

Environmental Ju stice

Potential areas of environmental justice concerns, to the extent possible, were considered in the human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” ( https://www3.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf ). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, inc luding, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who might be exposed when harvesting crops. Should these highest exposures indicate potential risks of c oncern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

Cumulative Risk Assessments

Triadimefon and triadimenol are both members of the triazole class of fungicides. EPA is not

curr ently following a cumulative risk approach for the triazole fungicides. However, this class of compounds does produce common metabolites: 1,2,4

- triazole, triazolylalanine, triazolylacetic acid, and/or triazolylpyruvic acid. These compounds are assessed sep arately from their parent compounds, in an aggregates strategy that takes into account the multiple active ingredients involved in their formation and the various sources of exposure.

Human Studies

The previous triadimefon/triadimenol risk assessments relied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure 1.1 (PHED) Database, Outdoor Residential Exposure Task Force (ORETF) database, Agricultural Handler Exposure Task Force (AHETF) database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 3



### .
Risk Assessment Updates, Data Requirements , and Label Revisions

Risk Assessment Updates During registration review, HED and AD anticipate conducting new risk assessments for triadimefon/triadimenol in order to evaluat e oral, dermal, and inhalation routes of exposure, including dietary, residential, and occu pational sou rces of exposure. HED and AD will consider both the conventional uses and the antimicrobial uses when evaluating aggregate
exposure.

3 Available at: http://www .epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handl er

exposure

- data and http://www .epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- post

application

- exposure.

### Page 19 of 34

Data Requirements OCSPP Guideline 860.1900: Field Accumulation in Rotational Crops (HED) OCSPP Guideline 870.3465: 90

- Day Inhalation Toxicity (HED) OCSPP Guideline 875.2100: Dislodgeable Foliar Residue Dissipation (HED; only if the uses of triadimefon on pineapple are still registered) OCSPP Guideline 875.1200: Dermal Exposure

- Indoor (AD) OCSPP Guideline 875.1400: Inhalation Exp o sure

- Indoor (AD) OCSPP Guideline 875.1700: Product Use Information (AD) OCSPP Guideline 875.2300: Indoor Surface Residue Dissipation (wood preservative) (AD)

Label Revisions Assuming that the uses of triadimefon on pineapple have been cancelled, the technical labels for triadimefon should be revised to delete references to formulations of product intended for treatment of pineapple

References

D314742. 23 November 2005. Ary, S. Triadimefon

– Summary of Analytical Chemistry and

Residue Data for the Re registration Eligibility Decision (RED) Document

. D314891. 17 November 2005. Ary, S. Triadimenol

– Summary of Analytical Chemistry and

Residue Data for the Tolerance Reassessment Eligibility Decision (TRED) Document. D331455. 1 August 2006. Barnes, Y and Piper, S. Triadimefon & Triadimenol: Aggregate

Acute, Chronic, and Short

- Term Risk Assessments Reflecting July, 2006 Risk Mitigation in Response to the Phase 4 Triadimefon RED. D349015. 4 August 2009. Barnes, P. Triad imefon & Triadimenol

. Submission of Plant

Metabolism Studies and a Confined Rotational Crop Study in Response to the Triadimenol TRED Dated August 2006. D351080. 3 August 2009. Figueroa, Z. and Scollon, E. Triadimefon: Human Health Risk

Assessment to Supp ort Reinstatement of Use on Residential Turf.

TXR # 0057320

. 2 February 2016. Triadimefon: Summary of the Hazard and Science Policy

Council (HASPOC) Meeting of November 12 th 

### , 2015: Recommendations on a Waiver Request for Immunotoxicity and Subchronic Inhal ation Studies.

TXR# 00 773 2 2. 22 March 2016. Triadimenol: Summary of the Hazard and Science Policy

Council (HASPOC) Meeting of November 12th, 2015: Recommendations on Waiver Requests for Subchronic Inhalation, Acute and Subchronic Neurotoxicity, and Metab olism Studies. D431445. 2 February 2016. Evans, E and Recore, S. Triadimefon : Tier I (Scoping) Review of

Human Incidents and Epidemiology

. D431446. 2 February 2016. Evans, E and Recore, S. Triadimenol : Tier I (Scoping) Review of

Human Incidents and Epidemiology

### Page 20 of 34

D351279. 10 March 2009. Lindheimer, T. Acute and Chronic Drinking Water Exposure and

Risk Assessments to the Registration Action of Preventol® A20 Preservative (EPA Reg # 39967

- TN).

D351282 . 21 April 2009. Mottl, N. Preventol® A20 and P reventol ®A20 Preservative:

Occupational and Residential Exposure Assessment for New Antimicrobial Uses (wood and wood composites) of Triadimefon for Proposed Products (39967

- AO and 39967

- TN).

Attachment s

Attachment 1. Triadimefon Toxicity Profile Tabl es

### Page 21 of 34

Attachment 1

. Triadimefon Toxicity Profile Tables

Table 1 a . Acute Toxicity Profile for Triadimefon. New Guideline No. Study Type MRID #(s) Results Toxicity Category

870.1100 Acute Oral

- rat 264276 LD50 = 1,470 mg/kg (Males) LD50 = 1,090 mg/kg (Females) III

870.1200 Acute Dermal

-

Rabbit 264276 LD50 > 2,000 mg/kg III

870.1300 Acute Inhalation

-

rat 41616002 LC50 > 3.570 mg/L IV

870.2400 Acute (Primary)

Eye Irritation

- rabbit 41782501 Slightly irritating IV

870.2500 Acute (Primary)

Dermal (Skin) Irritation

- rabbit 41616004 Not an irritant IV

870.2600 Skin (Dermal)

Sensitization

– guinea pig 41554001 Sensitizer Not Applicable

### Page 22 of 34

Table 1 b. Subchronic, Chronic, and Other Toxicology Profile for Triadimefon Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100a 90

- Day oral toxicity (rats) 00048624 Acceptable/guideline 0, 50, 200, 800 and 2000
ppm

(0, 2.5, 10, 40 and 100 mg/kg/day) NOAEL > 2000 ppm (100 mg/kg/day) (HDT). Decreased body weight gain and food consumption at 2000 ppm (100 mg/kg/day) was attributed to palatability.

The LOAEL was not observed.

870.3100 30

- Day oral toxicity (rats) 00048627 Acceptable/guideline 0, 3, 10, or 30 mg/kg/day NOAEL is 10 mg/kg/day

. The LOAEL is 30 mg/kg/day based on increased liver weights.

870.3100b 90

- Day oral toxicity (dogs) 00048625 & 00060226 (1974) Acceptable/guideline 0, 150, 600 and 2400 ppm (0, 3.75, 15, and 60mg/kg/day) NOAEL > 2400 ppm (60mg/kg/day) (HDT)

. Decreased body weight gain and food consumption at 2400 ppm (60mg/kg/day) was attributed to palatability.

The LOAEL was not observed.

870.3200 21

- Day dermal toxicity (rats) 42341501 (1992) Acceptable/guideline 0, 100, 300, or 1000 mg/kg bw/day NOAEL is 300 mg/kg/day. The LOAEL was 1000 mg/kg/day based on increased reactivity and activity in the females.

870.3700a Prenatal developmental in (rats) 00089023 (1981) Acceptable/guideline 0, 10, 25, 50, or 100 mg/kg bw/day Maternal NOAEL is 10 mg/kg/day and the LOAEL is 25 mg/kg/day based on dose

- related increase in both degree and duration of motor activity and/ or depression of maternal weight.

Developmental NOAEL is 50 mg/kg/day and the LOAEL is 100 mg/kg/day based on increased incidences of cleft palates; two fetuses from two different litters were found to have cleft palate.

870.3700a Prenatal developmental in (rats) 00149336 & 92188018 (1990) Acceptable/guideline 0, 10, 30, or 90 mg/kg bw/day Maternal NOAEL is 30 mg/kg/day and the LOAEL is 90 mg/kg/day based on decreased body weight gains.

Developmental NOAEL is 30 mg/kg/day

. The LOAEL is 90 mg/kg/day based on increased incidences of distended urinary bladders and abnormal ribs (extra ribs an d rib buds).

870.3700b Prenatal developmental in (rabbits) 41446201 & 42089601 (1990) Acceptable/guideline 0, 20, 50, or 120mg/kg bw/day Maternal NOAEL is 50 mg/kg/day and the LOAEL is 120 mg/kg/day based on minor decreases in initial body weight gains, placental weights, and fetal weights and on initial decreased food consumption.

Developmental NOAEL is 20 mg/kg/day. The LOAEL is 50 mg/k g/day based on dose

- related increases in the incidences of incomplete ossification of the pelvis pubes and anterior and posterior phalanges and irregular spinous processes on the scapula.

### Page 23 of 34

870.3800 Reproduction and fertility effects (rats) 00155075, 92188019 & 92188320 (1984) Acceptable/nonguideline 0, 50, or 1800 ppm (0, 2.5, 90 mg/kg/day)

The reproductive study in the rat is acceptable/ nonguideline in conjunction with the 3

- generation study (MRID 00032541). Parental/Systemic/ Reproductive toxicity NOAEL was not established because of the equivocal findings on body weights in the F 1 dams and ovary weights in the P dams at 2.5 mg/kg/day.

Offspring NOAEL is 2.5 mg/kg/day and the LOAEL is 90 mg/kg/day based on decreased pup weights and viabil ity in the F 1 and F 2 generations and decreased litter size in the F 2 generation.

Based on the combined two studies the Parental systemic/Reproductive toxicity NOAEL is 15 mg/kg/day and the LOAEL is 90 mg/kg/day. The Offspring NOAEL is 15 mg/kg/day and th e LOAEL is 90 mg/kg/day.
870.3800 Reproduction and fertility effects (3

- Gen) (rats) 00032541 (1979) Acceptable/nonguideline 0, 50, 300, or 1800 ppm (0, 2.5, 15, and 90 mg/kg/day)

The reproductive study in the rat is acceptable/ nonguideline in conjunction with the multi generation reproduction study (MRID 00155075) Parental systemic/Reproductive toxicity NOAEL is 15 mg/kg/day and the LOAEL is 90 mg/kg/day based on decreased fertility, body weights, body weight gains, and litter size.

Off spring NOAEL and LOAEL is equivocal due to severe reproductive effects (In the F 1 pups, at 90 mg/kg/day, the number of offspring per dam was decreased (p<0.05) in the F 1a and F 1b litters (decr. 20

- 31%) at post

- natal day (PND) 5

. At PND 28, viability was de creased (p<0.01) in the F 1a (90.7% treated vs 97.8% controls) and F 1b (56.4% treated vs 84.2% controls) pups

. Additionally, body weight gains of the F 1a pups were decreased (decr. 10%; p<0.05) during lactation).

Based on the combined two studies the Paren tal systemic/Reproductive toxicity NOAEL is 15 mg/kg/day and the LOAEL is 90 mg/kg/day. The Offspring NOAEL is 15 mg/kg/day and the LOAEL is 90 mg/kg/day.
870.4100b Chronic toxicity (dogs) 00032539 & 00126261 (1978) Acceptable/guideline

0, 100, or 330, or 1000 ppm (wk 1

– 54), or 2000 ppm (wk 55

- 104)

M: 0, 3.03, 11.42, 34.70 (wk 1

- 54) or 68.80 (wk 55

- 104) mg/kg bw/day

F: 0, 3.49, 11.96, 33.67 (wk 1

- 54) or 60.42 (wk 55

- 104) mg/kg bw/day NOAEL is 330 ppm (equivalent to 11.42/11.96 mg/kg/day in males/females).

LOAEL is 1000 ppm (equivalent to 34.70/33.67 mg/kg/day in males/females), based on increased alkaline phosphatase levels in both sexes; and decreased food consumption and increased cholesterol in females.

### Page 24 of 34

870.4200b Carcinogenicity (mice) 40752101& 40865101 (1986) Acceptable/guideline 0, 50, 300, or 1800 ppm

M: 13.5, 76.0, or 550.1 mg/kg/day F: 0, 19.6, 119.4 or 765 mg/kg/day NOAEL is 50 ppm (equivalent to 13.5/19.6 mg/kg/day in males/females).

LOAEL is 300 ppm (equivalent to 76.0/119.4 mg/kg/day in males/females) based on hepatocellular hypertrophy in both sexes; increased liver weights in males; and Kupffer cell proliferation, single cell necrosis and pigment accumulation in th e liver of females.

At the doses tested, the carcinogenic potential of MEB 6447 in mice is positive

. There was a treatment

- related increase (p<=0.05, study authors) in hepatocellular adenomas

. The incidence at the high dose (22% in males and 18% in femal es) exceeded the concurrent controls (4

- 6%) and the historical controls (0

- 18.4% [mean=5.9%] in males and 0

- 2% [mean=0.3%] in females)

. A positive trend (p<0.01, Agency reviewers, TXR # 007294) in combined liver nodules and hepatocellular adenoma was obser ved

. Furthermore, an increased incidence (p<0.01, Agency reviewers, TXR # 007294) of combined liver nodules and hepatocellular adenomas was observed at the high dose in both sexes

. Dosing was considered adequate based on hepatotoxicity in both sexes at >=3 00 ppm; and decreased body weights and body weight gain and increased overall food and water consumption in males at 1800 ppm.

870.4300 Combined Chronic/ Carcinogenicity (rats) 42153901 (1991) Acceptable/guideline 0, 50, 300, or 1800 ppm

M: 0, 2.7, 16.4, or 114.0 mg/kg/day F: 0, 3.6, 22.5, or 199.0 mg/kg/day NOAEL = 16.4/22.5 mg/kg/day in males/females.

LOAEL = 114.0/199.0 mg/kg/day in males/females based on increased food consumption in both sexes, incidence of fat in the hepatocytes in both sexes , alanine aminotransferase levels in males, cholesterol levels in females, and absolute and relative (to body) liver weights in females, and decreased body weight and body weight gains in females.

At the doses tested, the carcinogenic potential of MEB 64 47 is equivocal based on the incidence of thyroid adenomas and cystic hyperplasia in both sexes.
870.5100 Bacterial system 099412 7 099413 acceptable/ guideline negative

870.5395 Micronucleus assay 00048637 (1977) acceptable/ guideline negative

870.5450 Cytogenetics dominant lethal assay 00048628 (1976) acceptable/ guideline negative

870.5550 DNA damage/ Repair 00159343 (1985) negative

### Page 25 of 34

870.6200a acute neurotoxicity screening battery (rats 43495509 (1992) unacceptable/non

- guideline 0, 30, 100, 300 mg/kg/day No definitive NOAEL or LOAEL could be established

870.6200a acute neurotoxicity screening battery (rats) 43936101 (1996) Acceptable/guideline 0, 2, 31.2, 424.4 (females only) and 587.4 (males only) The NOAEL is 2 mg/kg.

The LOAEL for systemic/neurobehavioral findings is 31.2 mg/kg based on clinical signs, FOB, rearing, body temperature, MA, habituation, and spatial distribution in males and females.
870.6200b Subchronic neurotoxicity screening battery (rats) 44153501 (1996) Acceptable/guideline 0,50,800,or 2200 ppm

M: 0, 3.4, 54.6 or 149.8 mg/kg/day F: 0,4.3, 68.7, or 189.7 mg/kg/day NOAEL is 50 ppm (3.4 and 4.3 mg/kg/day, males/females, respectively).

LOAEL for neurotoxicity is 800 ppm (54.6 and 68.7 mg/kg/day males /females respectively) based largely on hyperactivity.

870.6300 Developmental Neurotoxicity Study in Rats 47377101 (2008) Acceptable/Non

- guideline 0, 100, 300, or 800 ppm

0, 8.0, 23.9, 71.3 mg/kg/day Parental NOAEL is 23.9 mg/kg/day and the LOAEL is 71.3 mg/kg/day based on decreases in body weight on GD 13 and LD 0 and body weight gain during GD 0

- 20.

Offspring NOAEL is 23.9 mg/kg/day and the LOAEL is 71.3 mg/kg/day based on post

- weaning clinical signs (deviated snout); decreases in pre

- weaning body weight (PND 11, 17, and 21) in both sexes, pre

- weaning body weight gain in both sexes; increased peak amplitude during auditory startle reflex testing in females; and increased number of trials to criterion during the retention phase of the avoidance test in females. 870.7485 Metabolism and pharmacokinetics (rats) 42409101(1992) Acceptable/guideline 5 or 50 mg/kg Radioactivity was not detected in the expired air

. The overall recovery of radioactivity was 97

- 112%

. The compound was predominantly excreted (90

- 98% dose) within 4 days

. The excretion profile of the repeated low

dose group was similar to the single low

- dose group; however, the excretion profiles were sex

- dependent

. Over a 4 day

- period, recovery in the urine was 24

- 28% dose in males and 57

- 66% i n females, and recovery in feces was 63

- 66% in males and 32

- 40% in females

. Thus, based on urinary excretion, absorption was at least 24% dose in males and 57% in females

. Less than 1% dose remained in the body 4 days after treatment

.

### Page 26 of 34

870.7485 Metabol ism and pharmacokinetics (rats) 00033057(1979) Acceptable/guideline 24.5

- 25.0 mg/kg Radioactivity was not detected in the expired air of animals

. Over a 7 day

- period, recovery in the urine was 29.8% dose in males and 39.9% in females, and recovery in feces was 52.7% in males and 34.5% in females

. Thus, based on urinary excretion, absorption was at least 29.8% dose in all animals.

Plasma levels of radioactivity were highest 1

- 2 hours post

dose (2.5

- 3.2 ppm), and the half

- life (calculated by the reviewer) wa s about 4 hours

. Tissue concentrations in males were generally similar to females

. The highest concentrations of radioactivity were found in the fat (43.5

- 45.0 ppm) at 4

- 8 hours post

- dose

. Approximately 50% of the radiolabeled compound in the fat of males was unchanged Bayleton and 50% was isomeric forms of the 2

- butanol derivative KWG 0519 (triadimenol); over 90% was Bayleton in females

. In addition, relatively high concentrations of radioactivity were observed in the liver (26.2

- 28.4 ppm) and skin (21

- 22 ppm) at 2 hours post

dose

. Tissue concentrations were <0.14 ppm at 7 days post

- dose.

In the urine, the major component of the acidified extract was KWG 0519 acid (6.1

- 7.7% dose)

. In the direct extract of urine, 3 minor metabolites were identified: p

chl orophenol, KWG 1323, and KWG 1342 (two isomers)

. In the direct extract of the feces, KWG 1323, KWG 1342, and KWG 0519 acid (5.7

- 20.0% dose) were identified

. KWG 1323 was the predominant metabolite in the feces of females (12.7% dose), and KWG 0519 acid was the predominant metabolite in the feces of males (20.0% dose)

. Thus, the major metabolites were the alcohol and acid of Bayleton, which were formed by the sequential hydroxylation and oxidation of the methyl group of the
t

- butyl chain.

### Page 27 of 34

Attachment 2. Triadimefon Toxicology Endpoint Tables.

Table 2 a . Summary of Toxicological Doses and Endpoints for Triadimefon in Dietary and Non

Occupational Human Health Risk Assessments.
Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF and Level of

Concern (LOC) for Risk Assessment Study and Toxicological Effects

Acute Dietary (all populations) NOAEL = 3.4 mg/kg/day

UF = 100 Acute RfD = 0.034

mg/kg/day

FQPA SF = 1X

aPAD = acute RfD FQPA SF

aPAD = 0.034 mg/kg/day Subchronic neurotoxicity study in rats. LOAEL = 54.6/68.7 mg/kg/day based largely on hyperactivity.

Chronic Dietary (all populations) NOAEL = 3.4 mg/kg/day

UF = 100 C hronic RfD = 0.034

mg/kg/day FQPA SF = 1X PAD = chronic RfD FQPA SF

cPAD = 0.034 mg/kg/day Subchronic neurotoxicity study in rats. LOAEL = 54.6/68.7 mg/kg/day based largely on hyperactivity.

Incidental Oral Short

- Term and Intermediate

- Term (1

- 30 days) (1

- month

– 6 months) NOAEL = 3.4 mg/kg/day Residential

MOE = 100 Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based largely on hyperactivity.

Dermal Short

- Term and Intermediate

- Term (1

- 30 days) (1

- month

– 6 months) Dermal NOAEL = 300 mg/kg/day Residential MOE = 100 21 Day Dermal Toxicity in rabbits.

The LOAEL= 1000 mg/kg/day based on increased reactivity and activity in the

females.

Inhalation Short

- Term and Intermediate

- Term (1

- 30 days) (1

- month

– 6 months) NOAEL = 3.4 mg/kg/day Residential

MOE = 100 Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based largely on hyperactivity.

Cancer (oral, dermal, inhalation) Classification: Category C “possible human carcinogen” based on statistically significant

increase in thyroid adenomas in male Wistar rats and statistically significant increases in

hepatocellular adenomas in both sexes of the NMRI mouse.
NOAEL = no observed adverse effect level

. LOAEL = lowest observed adverse effect level

. UF = uncertainty factor

. FQPA SF = FQPA Safety Factor

. PAD = population adjusted dose (a = acute, c = chronic)

. RfD = reference dose

. MOE = margin of exposure

. LOC = level of concern

.

### Page 28 of 34

Table 2 b

. Summary of Toxicological Doses and Endpoints for Triadimefon in Occupational Human Health Risk Assessments. Exposure Scenario Dose Used in Risk

Assessment, UF Level of Concern (LOC)

for Risk Assessment Study and Toxicological Effects

Dermal Short

- Term and Intermediate

- Term (1

- 30 days) (1

- month

– 6 months) Dermal NOAEL = 300 mg/kg/day Occupational MOE = 100 21 Day Dermal Toxicity in rabbits.

The LOAEL= 1000 mg/kg/day based on increased reactivity and activity in the

females.

Inhalation Short

- Term and Intermediate

- Term (1

- 30 days) (1

- month

– 6 months) NOAEL = 3.4 mg/kg/day Occupational

MOE = 100 Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg /kg/day based largely on hyperactivity.

Cancer (oral, dermal, inhalation) Classification: Category C “possible human carcinogen” based on statistically significant

increase in thyroid adenomas in male Wistar rats and statistically significant increases in

hepatocellular adenomas in both sexes of the NMRI mouse.
NOAEL = no observed adverse effect level

. LOAEL = lowest observed adverse effect level

. UF = uncertainty factor

. MOE = margin of exposure

. LOC = level of concern.



### Attachment 3

. Triadimenol Tox icity Profile Tables.

Table 3a : Acute Toxicity Profile

- Triadimenol Technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

- rat 00125411 LD 50 = 689 mg/kg (males) LD 50 = 752 mg/kg (females) III

870.1200 Acute dermal

- rabbit 00145086 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation

- rat 00145087 LC 50 > 2.58 mg/L (Limit Dose) IV

870.2400 Acute eye irritation

- rabbit 00145088 eye irritant (irritation cleared in 21 days or longer). II

870.2500 Acute dermal irritation

- rabbit 00145088 mild skin dermal irritation IV

870.2600 Skin sensitization

- guinea pig 00125413 Not a skin sensitizer Not Applicable

Table 3b : Subchronic, Chronic, and Other Toxicity Profile

- Triadimenol Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral toxicity rodents (rats) 00127769 (1977) Acceptable/guideline 0, 150, 600, or 2400 ppm M: 0, 12.16

, 49.23

, 203.07 mg/kg/day NOAEL is 600 ppm (equivalent to 49.23/71.33 mg/kg/day [M/F])

. The LOAEL is 2400 ppm (equivalent to 203.07/ 236.60 mg/kg/day [M/F]) based on initial body weight decreases in both

sexes.

### Page 29 of 34

Table 3b : Subchronic, Chronic, and Other Toxicity Profile

- Triadimenol Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

F: 0, 17.07

, 71.33

, 236.60 mg/kg/day

42192701 (1983) Acceptable/guideline 0, 120, 600, or 3000 ppm M: 0, 8.0, 39.6, 208.5 mg/kg/day F: 0, 9.4

, 46.4 , 221.1 mg/kg/day NOAEL is 120 ppm (equivalent to 8.0/9.4 mg/kg/day in the males/females). The LOAEL for this study is 600 ppm (equivalent to 39.6/46.4 mg/kg/day in the males/females) based o n increased liver weights and incidences of liver hypertrophy in the males and females and on fatty changes in the liver in the females.

870.3150 90

- Day oral toxicity (non

rodents

- dogs) 00125420 (1977) Acceptable/guideline 0, 150, 600, or 2400 ppm M: 0, 44.2, 178.5, or 717.0 mg/kg/day F: 0, 44.8, 179.0 or 702.1 mg/kg/day NOAEL is 600 ppm (equivalent to 44.2/44.8 mg/kg/day in the males/females). The LOAEL for this study is 2400 ppm (equivalent to 717.0/702.1 mg/kg/day in the males/females) base d on decreased body weights and body weight gains in the females, increased alkaline phosphatase, cholesterol, absolute kidney weights, and renal cysts in the males, and increased N

- demethylase and relative liver weights in the males and females.

870.3150 6 months oral toxicity (non

- rodents

- dogs) 00151247 (1984) Acceptable/guideline 0, 10, 30, or 100 ppm 0, 0.25, 0.75, or 2.5 mg/kg/day NOAEL is 100 ppm (approximately equivalent to 2.5 mg/kg/day). The LOAEL was not observed.

870.3200 15

- Day dermal toxicity (rabbits) 00151246 (1984) Acceptable/guideline 0, 50, or 250 mg/kg/day NOAEL is 250 mg/kg/day for males and females. The LOAEL was not observed.

870.3465 21

- Day inhalation toxicity (rats) 00125421 (1976) Unacceptable/not ungradable 0, 30, 68, or 230 mg/m 3 0, 0.030, 0.068, or 0.230 mg/L NOAEL is 0.230 mg/L/day, the highest dose tested. The LOAEL was not observed.

870.3700a 41498401 (1990) Acceptable/guideline Maternal NOAEL is 5 mg/kg/day and the LOAEL is 15 mg/kg/day based on decreased body weights and

### Page 30 of 34

Table 3b : Subchronic, Chronic, and Other Toxicity Profile

- Triadimenol Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Prenatal developmental in (rats) 0, 5, 15, 25, or 60 mg/kg/day

40307804 & 40887702 (1987) Acceptable/guideline 0, 30, 60, or 120 mg/kg/day adjusted (for gravid uterine weight) body weight gains.

Developmental NOA EL is 25 mg/kg/day and the LOAEL is 60 mg/kg/day based on increased incidences of extra ribs, a variation

.

Maternal NOAEL is 30 mg/kg/day and the LOAEL is 60 mg/kg/day based on decreased body weights, body weight gains, and food consumption.

Developmental NOAEL is 30 mg/kg/day and the LOAEL is 60 mg/kg/day based on increased incidences of supernumerary ribs

.

870.3700b Prenatal developmental in (rabbits) 42365001 (1992) Acceptable/guideline 0, 5, 25, or 125 mg/kg/day

40307805 & 408877 03 (1987) Acceptable/guideline 0, 8, 40, or 200 mg/kg/day Maternal NOAEL is 25 mg/kg/day and the LOAEL is 125 mg/kg/day based on decreased body weights, body weight gains, and food consumption.

Developmental NOAEL is 125 mg/kg/day (HDT)

. The developmental LOAEL was not observed.

Maternal NOAEL is 40 mg/kg/day and the LOAEL is 200 mg/kg/day based on clinical signs of toxicity, decreased body weights and food consumption, and increased post

- implantation loss and early resorptions.

Develo pmental NOAEL is 40 mg/kg/day and the LOAEL is 200 mg/kg based on skeletal abnormalities.

870.3800 Reproduction and fertility effects (rats) 00151248 (1984) Acceptable/ guideline 0, 20, 100, or 500 ppm (0, 1, 5 or 25 mg/kg/day) Parental/Systemic toxicity NOAEL is 5 mg/kg/day and the LOAEL is 25 mg/kg/day based on decreased body weights and body weight gains in the F1b generation.

Offspring toxicity NOAEL is 5 mg/kg/day and the LOAEL is 5 mg/kg/day based on decreased pup weight.

Reproductive toxicity NOAEL appears to be 5 mg/kg/day The LOAEL for reproductive performance was not observed.

870.4100b 00150484 & 00159012 (1984)

### Page 31 of 34

Table 3b : Subchronic, Chronic, and Other Toxicity Profile

- Triadimenol Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Chronic toxicity (dog) Acceptable/non

- guideline 0, 150, 600, or 2400 ppm 0, 3.8, 15.0, or 60.0 mg/kg/day The NOAEL is 3.8 mg/kg/day and the LOAEL is 15 mg/kg/day based on changes in enzyme levels.

870.4200 Carcinogenicity (mice) 44740901 (1998) Unacceptable/guideline 0, 80, 400, or 2000 ppm M: 0, 11.3, 60.2, or 340.3 mg/kg/day

F: 0, 17.2, 91.3 or 472 mg/kg/day NOAEL in males is 80 ppm (equivalent to 11.3 mg/kg/day) and in females is 400 ppm (equivalent to 91.3).

LOAEL in males is 400 ppm (equivalent to 60.2 mg/kg/day) based on hepatic changes and increased relative food consumption

. The chronic LOAEL in females is 2000 ppm (equivalent to 472.0 mg/kg/day) based on decreased body weights and body weight gains, increased relative food consumption, and hepatic changes.

No evidence of carcinogenicity

870.4200 Carcinogenicity (mice) 0 0126259 (1982) Acceptable/guideline 0, 125, 500, or 2000 ppm 0, 19, 75, or 300 mg/kg/day The NOAEL is 125 ppm (equivalent to 19 mg/kg/day).

The LOAEL is 500 ppm (equivalent to 75 mg/kg/day), based on increased alanine aminotransferase levels in both sexes and aspartate aminotransferase in females

.

At the doses tested, the carcinogenic potential of KWG 0519 is positive at 500 ppm

. Hepatic neoplastic lesions occurred in females due to
treatment

. The incidence of adenomas increased dose

- dependently (2

- 10% treated vs 0% concurrent controls and 4% historical controls)

. The incidence of hepatic carcinoma was increased at 500 and 2000 ppm (4

- 6% treated vs 2% concurrent controls)

. The incidence of combined hepatic adenomas and carcinomas was also increased at 500 and 2000 ppm (10

- 16% treated vs 2% controls)

. The Toxicology Branch Peer Review Committee (TXR #006772, dated July 6, 1988) concluded that KWG 0519 should be classified as a Group C carcinogen

. Dosing was considered adequate based on decreased body weights, and increased blood levels of hepatic enzymes and liver weights, and increased incidences of gross and microscopic abnormalities.

870.4300 Combined Chronic/Carcinogenicity (rats) 00126260 (1982) Acceptable/guideline 0, 125, 500, or 2000 ppm The NOAEL is 125 ppm (approximately equivalent to 6.25 mg/kg/day). The LOAEL is 500 ppm (approximately equivalent to 25 mg/kg/day), based on increased glutamate dehydrogenase and liver bile duct vacuolization in

### Page 32 of 34

Table 3b : Subchronic, Chronic, and Other Toxicity Profile

- Triadimenol Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

0, 6.25, 25, or 100 mg/kg/day males; and asp artate and alanine aminotransferase levels in females.

no evidence of carcinogenicity

870.5100 Bacterial system, mammalian activation gene mutation 00126264 (1979) Unacceptable/ guideline 0, 4, 20, 100, 500, or 2500 μg/plate (+S9) and 2500 μg/plate (

- S9) Negative

870.5300 In Vitro Mammalian Cell Gene Mutation 00126269 (1982) Acceptable/ guideline 7.8, 15.6, 31.3, 62.5, or 125.0 μg/mL (

- S9) 3.91, 7.81, 15.6, 31.3, or 62.5 μg/mL (+S9) Negative

870.5450 Cytogenetics dominant lethal assay 00126266 (1978) Unacceptable/up

- gradable 0 or 500 mg/kg Negative

870.5500 Other Genotoxicity DNA damage 00126271 (1981) Acceptable/guideline 0, 62.5, 125, 250, 500, or 1000 μg/plate Negative no evidence that DNA damage was induced

870.5550 Other Genotoxicity Unscheduled DNA Synthesis 00126271 (1982) Acceptable/guideline 0, 0.25, 0.5, 1, 2.5, 5, 10, 25, 50, 100, or 250 μg/mL. Negative no evidence that unscheduled DNA synthesis

870. 5900 Other Effects In vitro Sister Chromatid Exchange Assay 40815901 (1987) Acceptable/guideline 0, 100, 125, 150, 175, or 200 μg/mL (+S9) 0, 38, 75, 150, 225, or 300 μg/mL (

- S9) Negative

Other Studies Central Nervous Effects (mouse) 00145083 (1983) 3.75 to 60 mg/kg In mice, KWG 0519 (3.75 to 60 mg/kg) stimulated the spontaneous motility, increased their irritability and escape response and augmented certain reflexes; dose of 15 and 60 mg/kg potentiated the effect of amphetamine; and doses of 12 to 48 mg/kg antagonized that of reserpin

. The substance
pro longed the hexobartital sleeping time at 15 and 60 mg/kg

. In rats, the dose of 48 mg/kg had an excitatory effect.

A comparison with caffeine showed that the effect of the dose of 2.5 mg caffeine/ kg corresponded approximately to that of 12 to 15 mg/ KWG 0 519/

### Page 33 of 34

Table 3b : Subchronic, Chronic, and Other Toxicity Profile

- Triadimenol Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

kg, in the amphetamine potentiation test that of 4 mg KWG 0519/ kg, in the antagonism of ptosis 10 mg caffeine/ kg and 12 mg KWG 0519/ kg were comparable

. The no

- effect dose was ca. 1 mg/kg.



### Attachment 4. Triadimenol Toxicology Endpoint Tables.

Table 4a. Summary of Toxicological Doses and Endpoints for Triadime nol Dietary and Non

Occupational Human Health Risk Assessments.
Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF and Level of

Concern (LOC) for Risk Assessment Study and Toxicological Effects

Acute Dietary (all populations) NOAEL = 3.4 mg/kg/day

UF = 100 Acute RfD = 0.034

mg/kg/day

FQPA SF = 1X

aPAD = acute RfD FQPA SF

aPAD = 0.034 mg/kg/day Subchronic neurotoxicity study in rats. LOAEL = 54.6/68.7 mg/kg/day based largely on hyperactivity.

Chronic Dietary (all populations) NOAEL = 3.4 mg/kg/day

UF = 100 chronic RfD = 0.034

mg/kg/day

FQPA SF = 1X PAD = chronic RfD FQPA SF

cPAD = 0.034 mg/kg/day Subchronic neurotoxicity study in rats. LOAEL = 54.6/68.7 mg/kg/day based largely on hyperactivity.

Cancer (oral, dermal, inhalation) Classification: Category C “possible human carcinogen” based on increases in

hepatocellular adenomas in female mice

.

OCCUPATIONAL ENDPOINT/PODS SELECTED FOR SCREENING PURPOSES:

Table 4 b

. Summary of Toxicological Dos es and Endpoints for Triadimenol in Occupational Human Health Risk Assessments Exposure Scenario Dose Used in Risk

Assessment, UF Level of Concern (LOC)

for Risk Assessment Study and Toxicological Effects

Dermal Short

- Term and Intermediate

- Term (1

- 30 days) (1

- month

– 6 months) NOAEL = 30 mg/kg/day

DAF=50%* Occupational MOE = 100 Rabbit Developmental

Developmental LOAEL is 60 mg/kg/day based on increased incidences of supernumerary ribs in the absence of treatment related maternal toxicity.

### Page 34 of 34

Table 4 b

. Summary of Toxicological Dos es and Endpoints for Triadimenol in Occupational Human Health Risk Assessments Exposure Scenario Dose Used in Risk

Assessment, UF Level of Concern (LOC)

for Risk Assessment Study and Toxicological Effects

Inhalation Short

- Term Intermediate

- Term (1

- 30 days; 1

- 6 months ) NOAEL = 5 mg/kg/day Occupational

MOE = 100 Rat Developmental

LOAEL=15 mg/kg/day, based on decreased body weights.

Cancer (oral, dermal, inhalation) Classification: Category C “possible human carcinogen” based on increases in

hepatocellular adenomas in female mice

. *Estimated dermal absorption factor calculated by comparing the ratio of the oral rabbit developmental LOAEL and the rabbit dermal NOAEL (oral LOAEL/dermal NOAELx100)